tbuckley/cabot-search huggingface dataset:
Smooth muscle cell-specific deletion of S100A4 reroutes smooth muscle cell fate and modifies the inflammatory status of murine atherosclerotic lesions
Authors: LM Cardoso Dos Santos, P Azar, S Lemeille, ML Bochaton-Piallat
Journal: Cardiovascular Research (2022)

Abstract Funding Acknowledgements Type of funding sources: Other. Main funding source(s): Swiss National Science Foundation Foundation Centre de Recherches Médicales Carlos and Elsie de Reuter Background aims: S100A4, a small calcium binding protein, plays an important role in vascular smooth muscle cell (SMC) phenotypic switch but its implication in atherosclerotic plaque development and particularly in SMC phenotypic plasticity is not clear yet. By neutralizing S100A4 using a monoclonal antibody, we have previously shown a reduction in overall atherosclerotic burden. However, this strategy did not distinguish the different contribution between SMCs or other S100A4-expressing cells (e.g. macrophages). Methods Herein, we used a lineage tracing mouse model in which we induced a SMC specific deletion of S100A4 (SMC-S100A4Δ/Δ) in an ApoE-/- background. High cholesterol diet was maintained for 12 weeks, after which, SMC-S100A4Δ/Δ and control mice (SMC-S100A4wt/wt) were sacrificed and aortas processed for staining and single cell RNA sequencing (scRNA-seq). Results We showed that S100A4 deletion modulated plaque composition rather than plaque size. ScRNA-seq analysis from SMC-S100A4Δ/Δ and SMC-S100A4wt/wt showed a reduction in macrophages and dendritic cells and an increase in total SMCs, likely participating in fibrous cap stabilization. SMC populations showed a decrease in macrophage-like inflammatory phenotype and an increase in fibroblast-like repair phenotype, as well as retention of specific SMC markers, namely Acta2 and Myh11. Gene expression analysis revealed a reduction in the expression of inflammation markers, fatty acid metabolism, and extracellular matrix-related genes, and an increase in classical SMC markers and maintenance of the contractile phenotype. Conclusion We report an intrinsic function of S100A4 in the establishment of SMC fate within the plaque and, surprisingly, a global impact on the atherosclerotic plaque microenvironnement and inflammation status.
The spectrum of renal oncocytic neoplasms with indolent behavior waiting for 5th edition of WHO Classification of Urinary Tumours
Authors: A. Bressan, M. Valeri, M. Cieri, S. Pancetti, V. Belsito, R. Hurle, P. Casale, L.M. Terracciano, P. Colombo
Journal: European Urology (2022)
Microbiome associations between esophageal adenocarcinoma and esophageal squamous cell carcinoma.
Authors: Qian Wang, Yang Liu, Shanshan Xiao, Tao Wang
Journal: Journal of Clinical Oncology (2022)

e16050 Background: Microbiomes in tumor environment are thought to be associated with outcomes of precision therapy. Esophageal squamous cell carcinoma (ESCC) and Eophageal adenocarcinoma (EA) are the two subtypes of esophageal cancer. Although gene mutation and expression profiles have been well characterized, the microbial set between them are poorly studied. Methods: The microbial dataset of the identified species and their relative abundance using whole genome sequencing (WGS) and whole exome sequencing (WES) was obtained from TCMA database, which includes 17 EA samples and 32 ESCC samples. To investigate the microbial difference between EA and ESCC, The alpha diversity (Shanno and Simpson index) and beta diversity (PCoA, NMDS, Adonis) were calculated using the identified species to examine the overall difference between the two subtypes. The student's t-test were used to examine the relative abundance of single species Using the identified differential abundant microbial species, correlation analysis were performed to investigate whether synergistic effects exist for some species between the two subtypes. Moreover, taxonomy set enrichment analysis was used to find out whether the differential genus between EA and ESCC were associated with cancers. Finally, cox regression was used to investigated differential species between EA and ESCC affected the survival rate of EA group or ESCC group. Results: Through alpha and beta diversities, we didn’t find overall difference between EA and ESCC both in WGS and WES datasets. However, seventeen and two differential abundance species were found using Student’s t-test in WGS and WES datasets, respectively. The relative abundances of the differential species were mostly higher in ESCC than in EA. Correlation analyses showed that prevotella sp. HMSC069G02 and prevotella sp. HMSC077E08 were highly correlated. There were eight differential species ( prevotella aurantiaca, prevotella dentalis, prevotella marshii, etc.) were found in WGS and two species ( prevotella sp. C561, prevotella pleuritidis) in WES, respectively. The ten species all belong to prevotella genus, and taxon set enrichment analysis showed prevotella genus was associated with esophageal cancer, implies the identified differential species may be different in ESCC and EA patients. Among them, prevotella dentalis and prevotella buccae were found to be potentially risk factors in ESCC after Cox regression. Conclusions: This study investigated the microbiome difference between EA and ESCC cancers. Although we didn’t find the overall difference between the two subtypes, our preliminary results showed there exist some differential species between two subtypes. We found prevotella dentalis and prevotella buccae were the potential risk factors in ESCC, and the results can help further understand the therapy outcome differences between EA and ESCC from the microbial aspect.
Genetic and pharmacologic suppression of PPARγ enhances NELL-1-stimulated bone regeneration
Authors: Justine Tanjaya, Pin Ha, Yulong Zhang, Chenchao Wang, Yash Shah, Emily Berthiaume, Hsin Chuan Pan, Jiayu Shi, Jinny Kwak, Benjamin Wu, Kang Ting, Xinli Zhang, Chia Soo
Journal: Biomaterials (2022)

Recent investigations into mechanisms behind the development of osteoporosis suggest that suppressing PPARγ-mediated adipogenesis can improve bone formation and bone mineral density. In this study, we investigated a co-treatment strategy to enhance bone formation by combining NELL-1, an osteogenic molecule that has been extensively studied for its potential use as a therapeutic for osteoporosis, with two methods of PPARγ suppression. First, we suppressed PPARγ genetically using lentiviral PPARγ-shRNA in immunocompromised mice for a proof of concept. Second, we used a PPARγ antagonist to suppress PPARγ pharmacologically in immunocompetent senile osteopenic mice for clinical transability. We found that the co-treatment strategy significantly increased bone formation, increased the proliferation stage cell population, decreased late apoptosis of primary mouse BMSCs, and increased osteogenic marker mRNA levels in comparison to the single agent treatment groups. The addition of PPARγ suppression to NELL-1 therapy enhanced NELL-1's effects on bone formation by upregulating anabolic processes without altering NELL-1's inhibitory effects on osteoclastic and adipogenic activities. Our findings suggest that combining PPARγ suppression with therapeutic NELL-1 may be a viable method that can be further developed as a novel strategy to reverse bone loss and decrease marrow adiposity in age-related osteoporosis.
A randomised trial on modulating endogenous fibrinolysis in patients with acute coronary syndrome VaLiDate-R
Authors: Y X Gue, R Kanji, D Wellsted, M Srinivasan, S Wyatt, D Gorog
Journal: Cardiovascular Research (2022)

Abstract Funding Acknowledgements Type of funding sources: Private company. Main funding source(s): This study is funded by Bayer PLC, 400 South Oak Way, Green Park, Reading, Berkshire, RG2 6AD. Background Impaired endogenous fibrinolysis is novel biomarker that can identify patients with ACS at increased cardiovascular risk. The addition of very low dose rivaroxaban (VLDR) to dual antiplatelet therapy has been shown to reduce cardiovascular events but at a cost of increased bleeding and is therefore not suitable for all-comers. Targeted additional pharmacotherapy with VLDR to improve endogenous fibrinolysis may improve outcomes in high-risk patients, whilst avoiding unnecessary bleeding in low-risk individuals. Methods and Results The VaLiDate-R study is an investigator-initiated, randomised, open-label, single centre trial comparing the effect of 3 antithrombotic regimens on endogenous fibrinolysis in 150 patients with ACS. Subjects whose screening blood test shows impaired fibrinolytic status (lysis time &amp;gt;2000s), will be randomised to one of 3 treatment arms in a 1:1:1 ratio: clopidogrel 75 mg daily (Group 1); clopidogrel 75 mg daily plus rivaroxaban 2.5 mg twice daily (Group 2); ticagrelor 90 mg twice daily (Group 3), in addition to aspirin 75 mg daily. Rivaroxaban will be given for 30 days. Fibrinolytic status will be assessed during admission and at 2, 4 and 8 weeks. The primary outcome measure is the change in fibrinolysis time from admission to 4 weeks follow-up, using the Global Thrombosis Test. Conclusion If VLDR can improve endogenous fibrinolysis in ACS, future large-scale studies would be required to assess whether targeted use of VLDR in patients with ACS and impaired fibrinolysis can translate into improved clinical outcomes, with reduction in major adverse cardiovascular events in this high-risk cohort.
Delayed post-percutaneous nephrolithotomy hemorrhage: Are there any predictive factors difference between Arteriovenous fistula (AVF) and Pseudoaneurysm (PA)? A three-year Multicentric case-control study
Authors: A. Haghpanah, D. Irani, M. Rahmanian, A. Dehghani, B. Dejman, M.M. Hosseini
Journal: European Urology (2022)
Reproducibility of outcomes in sequential trials using CMV-targeted dendritic cell vaccination for glioblastoma.
Authors: John H. Sampson, Kristen A Batich, Duane Anthony Mitchell, James Emmett Herndon, Gloria Broadwater, Patrick Healy, Luis Sanchez-Perez, Smita Nair, Kendra Congdon, Pamela Norberg, Kent J. Weinhold, Gerald E. Archer, Elizabeth A. Reap, Weihua Xie, Roger E. McLendon, David A. Reardon, James J. Vredenburgh, Henry S. Friedman, Darell Bigner, Allan H. Friedman
Journal: Journal of Clinical Oncology (2022)

2005 Background: Vaccination with dendritic cells (DCs) fares poorly in primary and recurrent glioblastoma (GBM). Moreover, GBM vaccine trials are often underpowered due to limited sample size. Methods: To address these limitations, we conducted three sequential clinical trials utilizing Cytomegalovirus (CMV)-specific DC vaccines in patients with newly diagnosed GBM eligible to receive standard of care resection and adjuvant radiation therapy and temozolomide chemotherapy. Autologous DCs were generated and electroporated with mRNA encoding for the CMV protein pp65. Serial vaccination was given throughout adjuvant temozolomide cycles, and 111 Indium radiolabeling was implemented to assess migration efficiency of DC vaccines. Patients were followed for median overall survival (mOS) and OS. Results: Our initial study was the phase II ATTAC study (NCT00639639; total n = 12) with 6 patients randomized to vaccine site preconditioning with tetanus-diphtheria (Td) toxoid. This led to an expanded cohort trial (ATTAC-GM; NCT00639639) of 11 patients receiving CMV DC vaccines containing granulocyte-macrophage colony-stimulating factor (GM-CSF). Follow-up data from ATTAC and ATTAC-GM revealed 5-year OS rates of 33.3% (mOS 38.3 months; CI 95 17.5-undefined) and 36.4% (mOS 37.7 months; CI 95 18.2-109.1), respectively. ATTAC additionally revealed a significant increase in DC migration to draining lymph nodes following Td preconditioning ( P = 0.049). Increased DC migration was associated with OS (Cox proportional hazards model, HR = 0.820, P = 0.023). Td-mediated increased migration has been recapitulated in our larger confirmatory trial ELEVATE (NCT02366728) of 43 patients randomized to preconditioning (Wilcoxon rank sum, Td n = 24, unpulsed DC n = 19; 24h, P = 0.031 and 48h, P = 0.0195). In ELEVATE, median follow-up of 42.2 months revealed significantly longer OS in patients randomized to Td ( P = 0.026). The 3-year OS for Td-treated patients in ELEVATE was 34% (CI 95 19-63%) compared to 6% given unpulsed DCs (CI 95 1-42%). Conclusions: We report reproducibility of our findings across three sequential clinical trials using CMV pp65 DCs. Despite their small numbers, these successive trials demonstrate consistent survival outcomes, thus supporting the efficacy of CMV DC vaccine therapy in GBM. Clinical trial information: NCT00639639, NCT02366728.
Virtual Bronchoscopy of Neonatal Airway Malacia via High-Resolution, Respiratory-gated Magnetic Resonance Imaging
Authors: Nara S. Higano, Deep B. Gandhi, Qiwei Xiao, Chamindu C. Gunatilaka, Erik B. Hysinger, Robert J. Fleck, Jason C. Woods, Alister J. Bates
Journal: American Journal of Respiratory and Critical Care Medicine (2022)

"Virtual Bronchoscopy of Neonatal Airway Malacia via High-Resolution, Respiratory-gated Magnetic Resonance Imaging." American Journal of Respiratory and Critical Care Medicine, 206(5), pp. e42–e43
TREM2 in the pathogenesis of AD: a lipid metabolism regulator and potential metabolic therapeutic target
Authors: Rui-Yang Li, Qi Qin, Han-Chen Yang, Ying-Ying Wang, Ying-Xin Mi, Yun-Si Yin, Meng Wang, Chao-Ji Yu, Yi Tang
Journal: Molecular Neurodegeneration (2022)

Triggering receptor expressed on myeloid cells 2 (TREM2) is a single-pass transmembrane immune receptor that is mainly expressed on microglia in the brain and macrophages in the periphery. Recent studies have identified TREM2 as a risk factor for Alzheimer's disease (AD). Increasing evidence has shown that TREM2 can affect lipid metabolism both in the central nervous system (CNS) and in the periphery. In the CNS, TREM2 affects the metabolism of cholesterol, myelin, and phospholipids and promotes the transition of microglia into a disease-associated phenotype. In the periphery, TREM2 influences lipid metabolism by regulating the onset and progression of obesity and its complications, such as hypercholesterolemia, atherosclerosis, and nonalcoholic fatty liver disease. All these altered lipid metabolism processes could influence the pathogenesis of AD through several means, including affecting inflammation, insulin resistance, and AD pathologies. Herein, we will discuss a potential pathway that TREM2 mediates lipid metabolism to influence the pathogenesis of AD in both the CNS and periphery. Moreover, we discuss the possibility that TREM2 may be a key factor that links central and peripheral lipid metabolism under disease conditions, including AD. This link may be due to impacts on the integrity of the blood-brain barrier, and we introduce potential pathways by which TREM2 affects the blood-brain barrier. Moreover, we discuss the role of lipids in TREM2-associated treatments for AD. We propose some potential therapies targeting TREM2 and discuss the prospect and limitations of these therapies.
Short- and long-term outcomes of multiple myeloma patients undergoing modern treatments proceeding to ASCT: A retrospective analysis.
Authors: Hussein Awada, Adel Hajj Ali, Muhammad Faizan Ali, Ashish Kumar, Shubham Adroja, Gauranga Mahalwar, Arslan Babar, Faiz Anwer
Journal: Journal of Clinical Oncology (2022)

e20012 Background: Multiple Myeloma (MM) accounts for approximately 10% of all hematological malignancies. MM patients have heterogeneous outcomes that depend on several demographic, genetic and clinical factors. Here, we report the demographics along with the short and long-term outcomes in a cohort of patients who underwent Autologous Stem Cell Transplant (ASCT) over a period of 5 years. Methods: In this retrospective cohort, we assessed all MM patients who underwent ASCT at the Cleveland Clinic during the period between January 1, 2016 and January 15, 2021. Demographic characteristics, ISS staging, Cytogenetic risk categorization, Pre-ASCT treatment, short-term in-hospital complications, response (defined per IMWG response criteria) before and up to12 months after ASCT, as well as maintenance therapy were collected by reviewing electronic health records. Continuous variables are presented as mean with standard deviation, while categorical variables are presented as percentages. Categorical variables are compared using the chi-squared test while continuous variables are compared using the ANOVA and t-tests. Results: 379 patients who underwent ASCT within the studied time period were identified (Table). Most common cytogenetic abnormalities were del(13) (RB) 25.07%, t(11;14) 17.94% and gain(1q) 16.62%. A Lenalidomide, Bortezomib and dexamethasone (RVd) regimen was the most common to elicit response pre-ASCT (59.05%). Complete response (CR) was achieved in 27.82%, very good partial response (VGPR) in 34.71% and partial response (PR) in 37.47% of all patients pre-ASCT as compared to CR in 43.05%, VGPR in 28.05%, PR in 24.73% and progressive disease (PD) in 4.17% 3 months post-ASCT. All patients received intermediate (140 mg/m 2 ) or high-dose (200 mg/m 2 ) Melphalan conditioning. Average length of hospital stay was 14.56 ± 2.11. Of all patients, thrombotic events were seen in 1.3%, bleeding in 1.8%, neuropathy in 5.34%, mucocutaneous toxicities in 47.99%, cytopenias in 98.39% and infections in 32.25%. RBC and platelet transfusions were required in 36.1% and 88.9% of patients, respectively. Progression-free survival (PFS) was 96.89% at 3 months, 93.77% at 6 months, 92.55% at 9 months, and 88.47% at 12 months post-ASCT. PFS up to 12 months was not statistically different across ISS stages (p = 0.881) or cytogenetic risk categories (p = 0.347). Most common cause of death was progressive MM (73.47%). Conclusions: Responses in MM are boosted by ASCT. Its most common complications are transfusion-dependent thrombocytopenia and infections. Most patients survive beyond 1 year with PD rate of only 11.53%. Advanced ISS stage and high-risk cytogenetics do not confer higher PD in the 1 st 12 months post-ASCT.[Table: see text]
DIPG-40. Combined pharmacological and genetic screening to identify dependencies and combinations in ACVR1-mutant diffuse midline glioma
Authors: Rebecca Rogers, Diana Carvalho, Yura Grabovska, Elisabet Fernandez, Elisa Izquierdo, Alan Mackay, Chris Jones
Journal: Neuro-Oncology (2022)

Abstract Somatic mutations in ACVR1, which encodes the serine/threonine kinase ALK2, are found in 20-25% of DMG-H3K27 patients. Treatment of ACVR1-mutant patient-derived models with multiple chemotypes of ALK2 inhibitors (ALK2i) results in reduced cell viability in vitro and extended survival in orthotopic xenografts in vivo but, as single agents, these inhibitors were unable to achieve a complete anti-tumour response. Recently we reported that combinatorial treatment of ACVR1-mutant DIPG cells with vandetanib (RTK inhibitor) and everolimus (mTOR/ABC transporter inhibitor) was synergistic both in vitro and in vivo and was shown to be a feasible combination to trial clinically in this setting. To identify specific dependencies in ACVR1-mutant cells which may be translatable with novel synergistic drug combinations alongside ALK2i, we have implemented both candidate and unbiased drug and genetic screening approaches. Using a panel of patient-derived ACVR1-mutant and wild-type models, we identified synergy between multiple chemotypes of ALK2i (M4K2009/LDN-214117) and PI3K/mTOR (AZD8055/everolimus) and MEK inhibitors (trametinib), reflecting the common co-segregation of PIK3CA/PIK3R1 alterations in these tumours. Whole-genome CRISPR/Cas9 screening of ACVR1-mutant SU-DIPG-IV cells in combination with two ALK2i (M4K2009/LDN-193189), confirmed a specific MTOR genetic dependency, as well as for the protein phosphatase regulatory subunit PPP2R1A, known to play a role in MAPK pathway activation. Additional hits include the serine/threonine kinase PKMYT1, a negative regulator of the G2/M checkpoint via a functionally redundant phosphorylation of CDK1/CCNB1 alongside WEE1; confirmatory drug assays with the WEE1 inhibitor AZD1775 resulted in a synergistic interaction with ALK2i in ACVR1-mutant cells. Hits were integrated with DepMap using ‘gene-effect’ scores (Chronos) enabling filtering of common essential genes. Preliminary pathway enrichment analysis (MAGeCKFlute) identified ALK2i-specific vulnerabilities involving TGFB1/SMAD signalling and histone deacetylation. These data highlight functionally rational and novel combinatorial possibilities for children with ACVR1-mutant DMG, with systematic preclinical assessment required for prioritisation for the clinic.
GCT-14. The Impact of Residual Disease on the Outcomes of Central Nervous System Germinomas – A Single Institution Experience
Authors: Evan Cantor, Anne Cochrane, Andrea Ogle, Ashley Meyer, Nicole M Brossier, Margaret Shatara, Andrew Cluster, Mohamed S Abdelbaki
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND: CNS Germinomas are highly radio-sensitive tumors with an excellent survival rate of more than 90%. The current standard of care combines chemotherapy with reduced-dose radiotherapy to minimize the adverse effects and long-term effects associated with radiotherapy. In the latest Children’s Oncology Group clinical trial (ACNS1123 stratum 2), patients with residual or progressive disease following chemotherapy can be considered for a “second-look” surgery to assess tumor viability. Patients with residual disease who do not undergo second-look surgery receive 24 Gy of whole ventricular radiation with a 12 Gy boost compared to 18 Gy plus boost given to patients in complete remission or without viable tumor on second-look. Conversely, the International Society of Paediatric Oncology (SIOP) protocol does not stratify based on response to chemotherapy, and the Korean SMC GCT trial uses 18 Gy CSI plus boost for all patients regardless of chemotherapy response. METHODS: Single center retrospective chart review of germinoma patients treated at St Louis Children’s Hospital between 2011 and 2021. RESULTS: We analyzed data for all 15 germinoma patients treated between 2011 and 2021. Five patients had residual disease following chemotherapy. Of these five, one had complete remission at the end of radiotherapy, one had partial response, and three had stable disease. All patients remain relapse-free with time of follow-up ranging between 6.3-109.3 months from the end of therapy (median 24 months). CONCLUSION: None of the five patients with residual disease following chemotherapy demonstrated disease progression following chemotherapy and radiotherapy. Future prospective clinical trials are needed in order to test the possibility of treating germinomas patients who have residual disease after chemotherapy with a low dose of radiotherapy similar to that used in patients with complete remission.
A cross-sectional needs assessment and attitudes survey of paediatric urologists towards gaps and areas of perceived importance in adolescent transitional care
Authors: F. O'Kelly, R. Subramaniam, B. Haid, A. Bujons, B. Burgu, A-F. Spinoit, R. Nijman, C. Radmayr, M.S. Silay
Journal: European Urology (2022)
The effect of prolonged laser activation on intrafluid temperature. Is the low power safer? An in vitro experimental study
Authors: A. Tsaturyan, A. Peteinaris, E. Farsari, L. Pantazis, K. Pagonis, C. Adamou, A. Vagionis, S. Faitatziadis, A. Natsos, M. Obaidat, E. Liatsikos, P. Kallidonis
Journal: European Urology (2022)